title: Inhibition of Rac1 promotes BMP-2-induced osteoblastic differentiation.
abstract: Small G proteins of the Rho family are pivotal regulators of several signaling networks. The Ras homolog family (Rho) and one of its targets, Rho-associated protein kinase (ROCK), participate in a wide variety of biological processes, including bone formation. A previous study has demonstrated that the ROCK inhibitor Y-27632 enhanced bone formation induced by recombinant human bone morphogenetic protein-2 (BMP-2) in vivo and in vitro. However, the effect of other Rho family members, such as Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42), on bone formation remains unknown. In this study, we investigated whether Rac1 also participates in BMP-2-induced osteogenesis. Expression of a dominant-negative mutant of Rac1 enhanced BMP-2-induced osteoblastic differentiation in C2C12 cells, whereas a constitutively active mutant of Rac1 attenuated that effect. Knockdown of T-lymphoma invasion and metastasis 1 (Tiam1), a Rac-specific guanine nucleotide exchange factor, enhanced BMP-2-induced alkaline phosphatase activity. Further, we demonstrated that BMP-2 stimulated Rac1 activity. These results indicate that the activation of Rac1 attenuates osteoblastic differentiation in C2C12 cells.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Onishi
authors.forename: Y
authors.initials: Y
authors.lastname: Fujita
authors.forename: H
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; C525718:BMP2 protein, human; D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D020662:Guanine Nucleotide Exchange Factors; C487513:NSC 23766; D009479:Neuropeptides; D011743:Pyrimidines; C484602:Rac1 protein, mouse; C493716:Runx2 protein, mouse; D051785:Smad Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D015675:Osteocalcin; D000469:Alkaline Phosphatase; D020830:rac1 GTP-Binding Protein